Spirocyclic isoxazolines as antiparasitic agents

Abstract

The invention recites spirocyclic isoxazoline derivatives of Formula (1) stereoisomers thereof, veterinary or pharmaceutical acceptable salts thereof, compositions thereof, processes for making, and their use as a parasiticide in an animal. The variables W 1 , W 2 , W 3 , W, X, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , and n are as described herein.

We claim: 
     
       1. A compound of Formula (1) 
       
         
           
           
               
               
           
         
       
       wherein
 W 1 , W 2 , and W 3  are each independently C or N; 
 X is —S(O) p  or O and W is CH 2 , or W is —S(O) p  or O and X is CH 2 ; with the proviso that if W or X is O then one of W 1 , W 2 , and W 3  is N and if W 1 , W 2 , and W 3  are all C then one of X or W is —S(O) p ; 
 R 1a , R 1b  and R 1c  are each independently hydrogen, halo, cyano, hydroxyl, nitro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 0 -C 3 alkylC 3 -C 6  cycloalkyl, C 1 -C 6 haloalkoxy, —C(O)NH 2 , —SF 5 , or 
 R 2  is halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, nitro, hydroxyl, —C(O)NR a R b , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —S(O)R, or —OR; 
 R 3  is cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C(O)NR a R b , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkenyl, or C 2 -C 6 haloalkynyl; 
 R 4  is hydrogen, C 1 -C 6 alkyl, C 0 -C 6 alkylC 3 -C 6 cycloalkyl, —C(O)R 5 , —C(S)R 5 , —C(O)NR a R 5 , —C(O)C(O)NR a R 5 , —S(O) p R c , —S(O) 2 NR a R 5 , —C(NR 6 )R 5 , —C(NR 6 )NR a R 5 , C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle; 
 R 5  is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 -C 6 alkylC 3 -C 6 cycloalkyl, C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle; 
 R 6  is hydrogen, C 1 -C 6 alkyl, hydroxyl, cyano, nitro, —S(O) p R c , or C 1 -C 6 alkoxy; 
 R is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl optionally substituted with at least one halo substituent; 
 R a  is hydrogen, C 1 -C 6 alkyl, or C 0 -C 3 alkylC 3 -C 6 cycloalkyl; wherein the alkyl and alkylcycloalkyl is optionally substituted by cyano or at least one halo substituent; 
 R b  is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 0 -C 3 alkylphenyl, C 0 -C 3 alkylheteroaryl, or C 0 -C 3 alkylheterocycle, each optionally substituted, where chemically possible, with at least one substituent selected from hydroxyl, cyano, halo, or —S(O) p R; 
 R c  is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkylC 3 -C 6 cycloalkyl, C 0 -C 3 alkylC 3 -C 6 cycloalkyl, C 0 -C 3 alkylphenyl, C 0 -C 3 alkylheteroaryl, or C 0 -C 3 alkylheterocycle each optionally substituted with at least one substituent selected from cyano, halo, hydroxyl, oxo, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, —S(O) p R, —SH, —S(O) p NR a R b , —NR a R b , —NR a C(O)R b , —SC(O)R, —SCN, or —C(O)NR a R b ; 
 each of R 4  and R 5  C 1 -C 6 alkyl or C 0 -C 6 alkylC 3 -C 6 cycloalkyl moiety can be optionally and independently substituted by at least one substituent selected from cyano, halo, hydroxyl, oxo, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, hydroxylC 1 -C 6 alkyl-, —S(O) p R c , —SH, —S(O) p NR a R b , —NR a R b , —NR a C(O)R b , —SC(O)R, —SCN, or —C(O)NR a R b ; and 
 wherein each of R 4  and R 5  C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle moiety can be further optionally substituted with at least one substituent selected from cyano, halo, oxo, ═S, ═NR 6 , hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, hydroxylC 1 -C 6 alkyl-, C 1 -C 6 haloalkyl, —SH, —S(O) p R, and C 1 -C 6 haloalkoxy; 
 n is the integer 0, 1, or 2, and when n is 2, each R 2  may be identical or different from each other; and 
 p is the integer 0, 1, or 2; 
 
       stereoisomers thereof, and veterinary or pharmaceutical acceptable salts thereof. 
     
     
       2. The compound of Formula (1) of  claim 1  having Formula (1.1), (1.2), (1.3), or (1.4) 
       
         
           
           
               
               
           
         
       
       stereoisomers thereof, and veterinary or pharmaceutical acceptable salts thereof. 
     
     
       3. The compound of Formula (1.2) of  claim 2  having Formula (1.2b) 
       
         
           
           
               
               
           
         
       
       wherein W is O; stereoisomers thereof, and a veterinary or pharmaceutical acceptable salt thereof. 
     
     
       4. The compound of  claim 3  wherein
 R 1a , R 1b , and R 1c  are each independently hydrogen, fluoro, chloro, bromo, or CF 3 ; 
 R 3  is C 1 -C 6 haloalkyl; and 
 R 4  is —C(O)R 5 , stereoisomers thereof, and veterinary or pharmaceutical acceptable salts thereof. 
 
     
     
       5. The compound of Formula (1.3) of  claim 2  having Formula (1.3b) 
       
         
           
           
               
               
           
         
       
       wherein W is O; stereoisomers thereof, and a veterinary or pharmaceutical acceptable salt thereof. 
     
     
       6. The compound of  claim 5  wherein
 R 1a , R 1b , and R 1c  are each independently hydrogen, fluoro, chloro, bromo, or CF 3 ; 
 R 3  is C 1 -C 6 haloalkyl; and 
 R 4  is —C(O)R 5 , stereoisomers thereof, and veterinary or pharmaceutical acceptable salts thereof. 
 
     
     
       7. The compound of Formula (1.4) of  claim 2  having Formula (1.4b) 
       
         
           
           
               
               
           
         
       
       wherein W is O; stereoisomers thereof, and a veterinary or pharmaceutical acceptable salt thereof. 
     
     
       8. A compound of  claim 1  selected from the group selected from
 3′-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-1-[(methylsulfonyl)acetyl]-5′H-spiro[azetidin-3,7′-furo[3,4,b]pyridine]; 
 3′-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-1-[(methylsulfonyl)acetyl]-5′H-spiro[azetidin-3,7′-furo[3,4,b]pyridine]; 
 1-[(methylsulfonyl)acetyl]-3′-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-5′H-spiro[azetidin-3,7′-furo[3,4,b]pyridine]; 
 3′-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-1-isobutyryl-5′H-spiro[azetidin-3,7′-furo[3,4,b]pyridine]; 
 3′-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-1-isobutyryl-5′H-spiro[azetidin-3,7′-furo[3,4,b]pyridine]; 
 1-isobutyryl-3′-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-5′H-spiro[azetidin-3,7′-furo[3,4,b]pyridine]; 
 1-(2′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-7′H-spiro[azetidine-3,5′-furo[3,4-b]pyridine]-1-yl)-2-(methylsulfonyl) ethanone; 
 1-(2′-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-7′H-spiro[azetidine-3,5′-furo[3,4-b]pyridine]-1-yl)-2-(methylsulfonyl)ethanone; 
 2-(methylsulfonyl)-1-(2′-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-7′H-spiro[azetidine-3,5′-furo[3,4-b]pyridine]-1-yl)ethanone; 
 1-(2′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-7′H-spiro[azetidine-3,5′-furo[3,4-b]pyridine]-1-yl)-2-methylpropan-1-one; 
 1-(2′-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-7′H-spiro[azetidine-3,5′-furo[3,4-b]pyridine]-1-yl)-2-methylpropan-1-one; 
 2-methyl-1-(2′-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-7′H-spiro[azetidine-3,5′-furo[3,4-b]pyridine]-1-yl)propan-1-one; 
 1-(6′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1′H-spiro[azetidine-3,3′-furo[3,4-c]pyridine]-1-yl)-2-(methylsulfonyl)ethanone; 
 2-(methylsulfonyl)-1-(6′-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1′H-spiro[azetidine-3,3′-furo[3,4-c]pyridine]-1-yl)ethanone; 
 1-(6′-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1H-spiro[azetidine-3,3′-furo[3,4-c]pyridine]-1-yl)-2-(methylsulfonyl)ethanone; 
 1-(6′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1′H-spiro[azetidine-3,3′-furo[3,4-c]pyridine]-1-yl)-2-methylpropan-1-one; 
 2-methyl-1-(6′-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1H-spiro[azetidine-3,3′-furo[3,4-c]pyridine]-1-yl)propan-1-one; and 
 1-(6′-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1′H-spiro[azetidine-3,3′-furo[3,4-c]pyridine]-1-yl)-2-methylpropan-1-one, stereoisomers thereof, and veterinary or pharmaceutical acceptable salts thereof, or a compound selected from any one of the compounds in Table 1, Table 2, Table 3, or Table 4, stereoisomers thereof, and a veterinary or pharmaceutical acceptable salt thereof. 
 
     
     
       9. A veterinary composition comprising a compound of Formula 1 
       
         
           
           
               
               
           
         
       
       wherein
 W 1 , W 2 , and W 3  are each independently C or N; 
 X is —S(O) p  or O and W is CH 2 , or W is —S(O) p  or O and X is CH 2 ; with the proviso that if W or X is O then one of W 1 , W 2 , and W 3  is N and if W 1 , W 2 , and W 3  are all C then one of X or W is —S(O) p ; 
 R 1a , R 1b , and R 1c  are each independently hydrogen, halo, cyano, hydroxyl, nitro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 0 -C 3 alkylC 3 -C 6  cycloalkyl, C 1 -C 6 haloalkoxy, —C(O)NH 2 , —SF 5 , or —S(O) p R; 
 R 2  is halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, nitro, hydroxyl, —C(O)NR a R b , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —S(O) p R, or —OR; 
 R 3  is cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C(O)NR a R b , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkenyl, or C 2 -C 6 haloalkynyl; 
 R 4  is hydrogen, C 1 -C 6 alkyl, C 0 -C 6 alkylC 3 -C 6 cycloalkyl, —C(O)R 5 , —C(S)R 5 , —C(O)NR a R 5 , —C(O)C(O)NR a R 5 , —S(O) p R c , —S(O) 2 NR a R 5 , —C(NR 6 )R 5 , —C(NR 6 )NR a R 5 , C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle; 
 R 5  is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 -C 6 alkylC 3 -C 6 cycloalkyl, C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle; 
 R 6  is hydrogen, C 1 -C 6 alkyl, hydroxyl, cyano, nitro, —S(O) p R c , or C 1 -C 6 alkoxy; 
 R is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl optionally substituted with at least one halo substituent; 
 R a  is hydrogen, C 1 -C 6 alkyl, or C 0 -C 3 alkylC 3 -C 6 cycloalkyl; wherein the alkyl and alkylcycloalkyl is optionally substituted by cyano or at least one halo substituent; 
 R b  is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 0 -C 3 alkylphenyl, C 0 -C 3 alkylheteroaryl, or C 0 -C 3 alkylheterocycle, each optionally substituted, where chemically possible, with at least one substituent selected from hydroxyl, cyano, halo, or —S(O) p R; 
 R c  is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkylC 3 -C 6 cycloalkyl, C 0 -C 3 alkylC 3 -C 6 cycloalkyl, C 0 -C 3 alkylphenyl, C 0 -C 3 alkylheteroaryl, or C 0 -C 3 alkylheterocycle each optionally substituted with at least one substituent selected from cyano, halo, hydroxyl, oxo, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, —S(O) p R, —SH, —S(O) p NR a R b , —NR a R b , —NR a C(O)R b , —SC(O)R, —SCN, or —C(O)NR a R b ; 
 each of R 4  and R 5  C 1 -C 6 alkyl or C 0 -C 6 alkylC 3 -C 6 cycloalkyl moiety can be optionally and independently substituted by at least one substituent selected from cyano, halo, hydroxyl, oxo, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, hydroxylC 1 -C 6 alkyl-, —S(O) p R c , —SH, —S(O) p NR a R b , —NR a R b , —NR a C(O)R b , —SC(O)R, —SCN, or —C(O)NR a R b ; and 
 wherein each of R 4  and R 5  C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle moiety can be further optionally substituted with at least one substituent selected from cyano, halo, oxo, ═S, ═NR 6 , hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, hydroxylC 1 -C 6 alkyl-, C 1 -C 6 haloalkyl, —SH, —S(O) p R, and C 1 -C 6 haloalkoxy; 
 n is the integer 0, 1, or 2, and when n is 2, each R 2  may be identical or different from each other; and 
 p is the integer 0, 1, or 2; 
 
       stereoisomers thereof, and veterinary or pharmaceutical acceptable salts thereof. 
     
     
       10. The veterinary composition of  claim 9  further comprising at least one veterinary or pharmaceutical acceptable carrier. 
     
     
       11. The veterinary composition of  claim 10  further comprising at least one additional veterinary agent. 
     
     
       12. The veterinary composition of  claim 11  wherein said additional veterinary agent is selected from the group consisting of abamectin, ivermectin, avermectin, moxidectin, emamectin, eprinomectin, selamectin, doramectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfenbendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, indoxacarb, closantel, triclabendazole, clorsulon, refoxanide, niclosamide, praziquantel, epsiprantel, 2-desoxoparaherquamide, monepantel, pyripole, pyrafluprole, lufenuron, spiromesifen, tebufenozide, spinosad, spinetoram, imidacloprid, dinotefuran, metaflumizone, thibendiamide, chlorantraniliprole, indoxacarb, pyridalyl, pyrimidifen, pyrifluquinazon, milbemycin oxime, milbemycin, demiditraz, amitraz, fipronil, methoprene, hydroprene, kinoprene, permethrin, and pyrethrin, or mixtures thereof. 
     
     
       13. A method for the treatment of a parasitic infection or infestation in an animal comprising administering to said animal in need of such treatment an effective amount of a compound of Formula 1 
       
         
           
           
               
               
           
         
       
       wherein
 W 1 , W 2 , and W 3  are each independently C or N; 
 X is —S(O) p  or O and W is CH 2 , or W is —S(O) p  or O and X is CH 2 ; with the proviso that if W or X is O then one of W 1 , W 2 , and W 3  is N and if W 1 , W 2 , and W 3  are all C then one of X or W is —S(O) p ; 
 R 1a , R 1b , and R 1c  are each independently hydrogen, halo, cyano, hydroxyl, nitro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 0 -C 3 alkylC 3 -C 6  cycloalkyl, C 1 -C 6 haloalkoxy, —C(O)NH 2 , —SF 5 , or —S(O) p R; 
 R 2  is halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, nitro, hydroxyl, —C(O)NR a R b , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —S(O) p R, or —OR; 
 R 3  is cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C(O)NR a R b , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkenyl, or C 2 -C 6 haloalkynyl; 
 R 4  is hydrogen, C 1 -C 6 alkyl, C 0 -C 6 alkylC 3 -C 6 cycloalkyl, —C(O)R 5 , —C(S)R 5 , —C(O)NR a R 5 , —C(O)C(O)NR a R 5 , —S(O) p R c , —S(O) 2 NR a R 5 , —C(NR 6 )R 5 , —C(NR 6 )NR a R 5 , C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle; 
 R 5  is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 -C 6 alkylC 3 -C 6 cycloalkyl, C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle; 
 R 6  is hydrogen, C 1 -C 6 alkyl, hydroxyl, cyano, nitro, —S(O) p R c , or C 1 -C 6 alkoxy; 
 R is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl optionally substituted with at least one halo substituent; 
 R a  is hydrogen, C 1 -C 6 alkyl, or C 0 -C 3 alkylC 3 -C 6 cycloalkyl; wherein the alkyl and alkylcycloalkyl is optionally substituted by cyano or at least one halo substituent; 
 R b  is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 0 -C 3 alkylphenyl, C 0 -C 3 alkylheteroaryl, or C 0 -C 3 alkylheterocycle, each optionally substituted, where chemically possible, with at least one substituent selected from hydroxyl, cyano, halo, or —S(O) p R; 
 R c  is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkylC 3 -C 6 cycloalkyl, C 0 -C 3 alkylC 3 -C 6 cycloalkyl, C 0 -C 3 alkylphenyl, C 0 -C 3 alkylheteroaryl, or C 0 -C 3 alkylheterocycle each optionally substituted with at least one substituent selected from cyano, halo, hydroxyl, oxo, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, —S(O) p R, —SH, —S(O) p NR a R b , —NR a R b , —NR a C(O)R b , —SC(O)R, —SCN, or —C(O)NR a R b ; 
 each of R 4  and R 5  C 1 -C 6 alkyl or C 0 -C 6 alkylC 3 -C 6 cycloalkyl moiety can be optionally and independently substituted by at least one substituent selected from cyano, halo, hydroxyl, oxo, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, hydroxylC 1 -C 6 alkyl-, —S(O) p R c , —SH, —S(O) p NR a R b , —NR a R b , —NR a C(O)R b , —SC(O)R, —SCN, or —C(O)NR a R b ; and 
 wherein each of R 4  and R 5  C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle moiety can be further optionally substituted with at least one substituent selected from cyano, halo, oxo, ═S, ═NR 6 , hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, hydroxylC 1 -C 6 alkyl-, C 1 -C 6 haloalkyl, —SH, —S(O) p R, and C 1 -C 6 haloalkoxy; 
 n is the integer 0, 1, or 2, and when n is 2, each R 2  may be identical or different from each other; and 
 p is the integer 0, 1, or 2; 
 
       stereoisomers thereof, and veterinary or pharmaceutical acceptable salts thereof. 
     
     
       14. The method of  claim 13  wherein said animal is a companion animal or livestock and the compound is administered topically, orally, or subcutaneously. 
     
     
       15. The method of  claim 14  wherein the companion animal is a dog, cat, or horse. 
     
     
       16. The method of  claim 14  wherein livestock is cattle. 
     
     
       17. The method of  claim 14  wherein the compound is administered topically. 
     
     
       18. The method of  claim 14  wherein the compound is administered orally. 
     
     
       19. The method of  claim 14  wherein the compound is administered subcutaneously.